Progranulin (PGRN) is a cytokine widely expressed in mammalian tissues. PGRN plays important roles in embryonic development, sexual differentiation, tumorigenesis, glucose metabolism and obesity, immunity, infection and inflammation. Altered PGRN production/function has been associated with trauma, infection, malignancy, wounding, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, and systemic lupus erythematosus. How PGRN regulates these biological processes is poorly understood. The major hypothesis of our proposal is that PGRN controls systemic inflammation and tissue stability in a substantial part through its ability to modulate IL-10 production. Specifically, we believe that this important regulatory pathway is structured hierarchically in the following order: CCAAT/enhancer-binding protein (C/EBP) a IL-10. To test the hypothesis we will investigate the molecular mechanisms whereby the transcriptional regulator C/EBP? targeted by PGRN stimulates IL-10 gene expression at the molecular level via TNF receptor-mediated signaling. Then, we will elucidate the mechanisms of PGRN-regulated systemic inflammatory responses and their IL-10 and TNFR dependency via C/EBPa. We will also assess if compensating the IL-10 deficit in PGRN-deficient mice can ease their susceptibility to microbially induced septic shock; and whether administration of recombinant PGRN can protect mice from sepsis-induced lethality. The long-term objective of this application is to gain insights into how the host regulates immune responses to inflammatory assaults, such as microbes and trauma, and to lay the foundation for developing better therapies for systemic inflammation-related maladies. The current project focuses on the cellular and molecular mechanisms whereby PGRN regulates the synthesis of IL-10 in macrophages in vitro and protects the host in systemic inflammatory disorders. The proposed studies will provide greater understanding of the novel role and mechanism of PGRN in the systemic inflammatory response syndrome and aid in the development of innovative strategies for effective interventions in sepsis, restoration of tissue homeostasis, and reestablishment of impaired immunological competency.